PB1816: RUNX1 GERMLINE VARIANT AND CLONAL EVOLUTION TO ACUTE MYELOID LEUKEMIA – A FPDMM FAMILY STUDY
Authors: Maria Luís Amorim, Joana Araújo, Lopes Mariana, Quental Rita, Fátima Ferreira, Manuel Sobrinho-Simões, Ricardo Pinto, Fernanda Trigo
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: The identification of myeloid neoplasms with germline predisposition is important for patient management, especially when considering a matched-related donor hematopoietic stem cell transplantation. These familial syndromes also represent a unique opportunity to study clonal evolution and leukemogenesis. As the availability of germline-focused analysis is mostly restricted to reference centres, the incidence of these syndromes is unknown. Here we present a case of a family with RUNX1 familial platelet disorder with associated myeloid malignancies (RUNX1-FPDMM) identified using a widely available Next-Generation-Sequencing (NGS) myeloid somatic panel. Aims: To study a family with thrombocytopenia and myeloid malignancies. The proband is a 11 years-old child followed at the Pediatrics Hematology clinic due to mild thrombocytopenia. Proband’s father and paternal grandfather were both diagnosed with myelodysplastic syndrome that evolved to overt AML, preceded by thrombocytopenia, and both were transplanted with matched-related donors. The grandfather died of transplant complications and the father is currently alive and in complete remission. Methods: DNA was extracted from peripheral blood (PB) of the child and retrospectively from the father’s bone marrow (BM) at the time of AML diagnosis, and was analysed using NGS with Oncomine Myeloid Assay (Thermofisher) and Ion Reporter 5.18.4.0. software. Germline origin of the variant was confirmed by Sanger Sequencing on DNA obtained from hair roots. The proband was referred to a genetics counselling clinic. Results: A nonsense variant, c.814C>T p.(Gln272Ter), was identified in the RUNX1 gene in the child’s PB sample, with a variant allele frequency (VAF) of 55% The same variant was found in hair roots samples from child and father confirming the germline origin. This variant was classified as likely pathogenic (LP) accordingly to the ClinGen Myeloid Malignacy Curation Expert Panel for Germline RUNX1 Variants. Additional somatic pathogenic variants in other genes - PHF6, TP53, TET2 and EZH2 – were identified in father’s BM sample at the time of AML diagnosis. Summary/Conclusion: The identification of a heterozygous germline LP variant in RUNX1 in a family with a clinical suspicion of a germline risk of myeloid malignancies allowed us to establish the diagnosis of RUNX1-FPDMM, an autosomal dominant disease. Mild-to-moderate thrombocytopenia is the highest penetrant feature of this disorder, and was present in the proband, the father and the grandfather. The identification of these pre-leukemic conditions is very important for a closer surveillance of the family and, in case of eventual malignant transformation, provides the opportunity for a selection of a matched-related donor that does not carry the pathogenic variant. With the additional mutations detected at the time of AML diagnosis in the father’s BM we had the opportunity to study the clonal evolution and the leukemogenic process. NGS myeloid somatic panel are increasingly being used in the diagnosis and management of patients with myeloid neoplasms. Although these panels do not include all the genes or regions associated with germline predisposition, the careful review of NGS results, together with the personal and family history, can provide a useful tool to improve the detection of these germline predisposition syndromes, of which the real incidence is unknown and probably underestimated.Keywords: RUNX1